新型氮唑类抗真菌化合物的设计合成及构效关系研究

项目名称： 新型氮唑类抗真菌化合物的设计合成及构效关系研究

项目编号： No.81072534

项目类型： 面上项目

立项/批准年度： 2011

项目学科： 化学工业

项目作者： 孟庆国

作者单位： 烟台大学

项目金额： 10万元

中文摘要： 基于前期工作基础和已有的计算机辅助药物设计结果，保留氟康唑的药效团三氮唑、2,4-二氟苯基和羟基，以N,N-取代叔胺侧链替代氟康唑3位的三氮唑，设计、合成了103个新型氮唑类抗真菌化合物。化合物的结构经核磁、质谱、元素分析或高分辨质谱等确证。以临床上常用的氟康唑、伊曲康唑、伏立康唑、酮康唑、特比萘酚和两性霉素B为阳性对照药，参照美国国家临床实验室标准委员会(NCCLS)制定的微量稀释法测定了90个化合物的体外最小抑菌浓度（MICs）。初步总结了该类氮唑类抗真菌化合物的构效关系。发现氟康唑3位的三唑环被含有炔丙叔胺侧链取代的氮唑类化合物具有较好的体外抗真菌活性（烟曲霉菌除外），含有其它烃基取代叔胺侧链衍生物的体外抗真菌活性较弱或没有活性，氟康唑3位的三唑环被亲水性基团（如胸腺嘧啶）取代，衍生物抗真菌活性丧失。氟康唑3位引入炔丙叔胺侧链有利于提高该类目标化合物体外抗真菌活性，进一步研究该类新型氮唑类抗真菌化合物的作用机制和体内抗真菌活性，具有重要的理论意义。正式发表1篇SCI论文，2篇论文分别被有机化学和中国新药杂志接受待出版，另一篇论文投稿至Medicinal Chemistry。

中文关键词： 三唑类；衍生物；合成；抗真菌活性；构效关系

英文摘要： Based on the previous study and the results of computer-aided drug design, 103 novel azoles antifungal agents have been designed and synthesized. The triazole ring, the 2, 4-difluorophenyl group and the hydroxyl group, pharmacophores of fluconazole, were retained and another triazole ring was modified as different N, N-substituted tertiary amines. The structures of all the novel derivatives were elucidated by NMR, ESI-MS, elemental analysis or HRMS. Fluconazole (FCZ), itraconazole (ICZ), voriconazole (VCZ), ketoconazole (KCZ), terbinafine (TRB), mphotericin B (AMB) were used as the positive controls. The in vitro minimal inhibitory concentrations (MICs) against eight fungi of 90 novel compounds were determined by the micro-broth dilution method in 96-well microtestplates according to the methods defined by the National Committee for Clinical Laboratory Standards(NCCLS). Preliminary in vitro antifungal activities bioassay indicated that azoles antifungal agents containing substituted propargyl tertiary amine showed good in vitro antifungal activities against eight fungi except Aspergillus fumigatus (7544) than fluconazole and compounds containing other alkyl group substituted tertiary amine showed only moderate even no activity against nearly all the tested fungal pathogens, the azoles derivatives containing hydrophilic groups (thymine) showed no activity against all the tested fungal pathogens, and the preliminary structure activity relationships (SAR) were summed up. The preliminary results indicated that the introduction of propargyl substituted tertiary amine groups to the C-3 position of fluconazole can enhance in vitro antifungal activities and the mechanism of action and in vivo activities of these derivatives were worth of further research. One paper (SCI) has been published on Acta Cryst, two papers have been revised and accepted by Chinese Journal of Organic Chemistry and Chinese Journal of New Drugs, respectively. Another paper has been submitted to Medicinal Chemistry.

英文关键词： triazole;derivative;synthesis; antifungal activity; structure activity relationship(SAR)